Pancreatic amylase and lipase activities were measured in sera of 307 Caucasian insulin-dependent diabetes mellitus patients (IDDM) at clinical onset, 303 nondiabetic siblings of registered patients, and 207 control subjects under age 40 years. In all subject groups lipasemia and pancreatic (but not salivary) amylasemia increased with age and were significantly correlated. Using age-dependent reference ranges, reduced pancreatic enzyme levels were measured in 18% of patients, 6% of siblings, and only 2% of control subjects (p

We have previously studied the expression of protein tyrosine kinases in different preparations of insulin producing cells by polymerase chain reaction (PCR). Among the tyrosine kinases thus identified were the fibroblast growth factor receptor-4 (FGFR-4), c-Kit, the insulin-like growth factor (IGF-I) receptor, and the cytoplasmic tyrosine kinase Jak2, which associates with the activated receptor for growth hormone (GH). To elucidate the putative biological effects of the receptors identified, fetal islet-like structures were cultured in the absence or presence of the ligands to the receptors identified, namely, acidic FGF (aFGF), stem-cell factor (SCF), IGF-I, and GH, whereafter insulin and DNA contents as well as insulin secretion to the culture medium were determined. Nerve growth factor (NGF), the ligand to the tyrosine kinase receptor Trk-A, was also included. aFGF and GH were found to stimulate insulin release to the culture medium, whereas SCF augmented insulin contents/DNA as well as islet DNA contents. No effects of NGF or IGF-I were detected. Immunohistochemical studies of fetal rat pancreas showed localization of the c-Kit protein to the pancreatic ducts, whereas immuno-reactivity against FGFR-4 could be detected in both endocrine and exocrine parts of the pancreas as well as in the pancreatic ducts. It is concluded that tyrosine kinase receptors may be involved in the maturation of pancreatic beta cells.

Advances in the field of organ transplantation have been made possible by progress in cold preservation as well as advances in immunosuppression, postoperative surgical care, and refinement of surgical techniques. The optimal solution for cold storage of pancreatic islets has not been defined, although recent studies have suggested that University of Wisconsin (UW) solution or derivatives may be significant advances. Zinc has a central role in the storage, synthesis, and secretion of insulin and is taken up preferentially by isolated islets to levels 30-fold higher than those of extracellular zinc. Since the currently used cold storage solutions do not contain zinc, we have investigated the effect of adding zinc to Hanks and UW solution and assessed the viability status of the islets at 0 h and at 1, 3, and 6 days. Islets of standard diameter were suspended in four solutions: Hanks solution, Hanks +20 microM zinc, UW solution, and UW +20 microM zinc. Viability was assessed by supravital staining, and each islet was scored at 0 h and at 1, 3, and 6 days. The results showed that UW solution was superior to Hanks solution for the preservation of pancreatic islets up to 6 days, but the addition of zinc was not beneficial. Despite the integral role of zinc in islet metabolism, we were unable to find a beneficial role for zinc in cold storage solutions for the purposes of islet preservation.

Although previous reports suggest interactions between the endocrine and the exocrine pancreas, insulin's effect on pancreatic exocrine function remains unclear. Chronic pancreatic fistulae were created in five dogs; these animals were studied using the euglycemic, hyperinsulinemic clamp technique. After a 30-min unstimulated period, both groups received a 60-min, 1.5 mU/kg/min insulin (clamp) or vehicle (control) infusion. Cholecystokinin (CCK) or meal stimulation was then begun. Intravenous CCK was initiated at 12.5 ng/kg/h; the CCK dose was doubled every 30 min until 100 ng/kg/h was achieved. The intraduodenal liquid test meal (1.5 kcal/ml; 15% protein, 32% fat, 53% carbohydrate) was administered at 100 ml/h. Unstimulated (0- to 30-min) serum glucose and insulin levels and pancreatic bicarbonate and protein outputs did not differ between groups. Clamp (30- to 90-min) and stimulated (90- to 210-min) insulins were significantly elevated in clamp groups (p

This work extends a recent observation that Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which have been established as an animal model of non-insulin-dependent diabetes mellitus, show no expression of the cholecystokinin (CCK)-A receptor gene in the pancreas. The CCK-A receptor is known to be involved in regulating pancreatic exocrine function and growth. We examined the growth of the pancreas in terms of wet weight, enzyme compositions, and protein and DNA contents at 5-6 and 24-25 weeks of age in OLETF rats and control (Long-Evans Tokushima; LETO) rats. The pancreatic wet weight increased significantly with age in both OLETF and LETO rats but was significantly lower in OLETF rats than in LETO rats. The total DNA contents in the whole pancreas (cell numbers) were comparable for both strains and increased significantly with age. However, the ratio of protein content to DNA content (the cell size) significantly increased with age in LETO rats, with no increase in OLETF rats. The changes in chymotrypsin, amylase, and insulin with respect to age were in the same direction in both strains: a decrease or no change in total and/or cellular contents of chymotrypsin and insulin and increases in amylase. These results suggest that the CCK-A receptor plays some role in the increase in cell size associated with normal growth of the pancreas from 5 to 25 weeks of age (after weaning).

To elucidate the clinical significance of neural invasion in pancreatic carcinoma, a clinicopathological study was performed. Neural invasion is a common feature of pancreatic carcinoma whose clinical significance has not yet been determined. Over a period of > 10 years, 129 of 204 (63%) patients with pancreatic carcinoma underwent resection by extensive radical surgery. A clinicopathological study of those specimens of pancreatic carcinoma was performed, with particular reference to neural invasion. Intrapancreatic neural invasion was observed in 116 of 129 (90%), of which 80 (69%) showed extrapancreatic nerve plexus involvement. A statistically significant (p 3 years after operation had no extrapancreatic nerve plexus invasion even when portal vein wall invasion was observed.

Intraductal mucin-hypersecreting neoplasm of the pancreas (IMHN) is a unique tumor that is composed of tumor cells with different cell atypia. K-ras and p53 alterations have been shown to occur in pancreatic duct cell carcinoma (PDC), but they have not been well documented in the individual lesion of IMHN. The aim of this study was to examine the relation of the genetic alterations of K-ras and p53 in IMHN to the tumorigenesis of the pancreas. In 32 microscopically dissected lesions of seven cases of IMHN, the K-ras mutation was investigated by primer-mediated, mutant-enriched, polymerase chain reaction-restriction fragment length polymorphism. Mutant p53 expression was examined in the adjacent serial sections by immunohistochemistry. In IMHN, alterations of K-ras and p53 were frequently observed (71.9 and 50%, respectively). The frequency became higher as the grade of cell atypia increased. Simultaneous alterations of the two genes were detected in carcinoma and its accompanying hyperplastic and dysplastic lesions. It is suggested that alterations of K-ras and p53 may be early events in the tumorigenesis of IMHN and may cooperate to produce neoplastic transformation of the pancreatic duct epithelium.

The distribution and clinicopathologic features of pancreatic fibrosis were studied histopathologically in 137 autopsy cases of chronic alcohol abuse. Fibrosis was observed in 90 of the cases and was classified as perilobular sclerosis (PS) and intralobular sclerosis (IS). Fibrosis of the PS type was irregular and sometimes patchy and extended into the intralobular area in advanced cases. In some advanced cases, complete replacement of the pancreatic tissue by extensive fibrosis was seen. Fibrosis of the IS type was uniformly distributed. The tissues in some cases showed prominently periacinar fibrosis. In these cases, the pancreatic parenchyma had not been completely replaced by extensive fibrosis. Clinicopathologic comparisons revealed the following results: accompanying liver cirrhosis was greater in the IS than in the PS of fibrosis. However, a higher frequency of protein plugs, pancreatic stones, extensive fibrosis replacement, peripancreatic fibrosis, splenic vein involvement, choledochus involvement, pseudocyst, and ductal hyperplasia was found in the PS type compared to the IS type. In conclusion, the findings on the perilobular and intralobular distribution of fibrosis and differences in various components or accompanying diseases in pancreatic fibrosis suggest that this entity shows two distinct pathologic patterns with differing mechanisms.

A standardized method for pathologic evaluation and staging of pancreaticoduodenectomy (PD) specimens is critical for accurate reporting of the number and location of lymph nodes and margins of resection. We examined the impact of standardized pathologic evaluation (SPE) of PD specimens on the identification of regional lymph nodes and describe our detailed system for the pathologic analysis of the PD specimen. Forty consecutive patients underwent PD for histologically confirmed adenocarcinoma of the pancreatic head between April 1990 and August 1993. Fifteen consecutive specimens were examined before the introduction of the SPE, and 25 consecutive specimens underwent SPE. Resection margins were evaluated by frozen-section analysis, and then the specimen was divided into six regions on an anatomic dissection board for lymph node identification. The 25 specimens examined according to the SPE had a significantly increased number of lymph nodes identified (P = 0.0001) compared with the 15 specimens examined without the SPE. Twelve of the 25 specimens contained positive lymph nodes, 6 of which were confined to the pancreaticoduodenal region. No positive nodes were found in the periaortic region. There were no differences in pathologic variables between patients found to have negative and those with positive regional lymph nodes. SPE of PD specimens provides a method for improved lymph node identification, ensures accurate prospective evaluation of margins of resection, and provides a complete analysis of potentially important pathologic variables. We offer this system as a standardized model for groups engaged in protocol-based clinical research examining innovative multimodality treatment strategies for patients with resectable pancreatic cancer.

Clinical and laboratory data or imaging results cannot provide a positive diagnosis of septic complications of pancreatic and peripancreatic necrosis in patients with acute pancreatitis. Confirmation can be obtained only after percutaneous computed tomography (CT)-guided aspiration of the necrotic tissues or fluid collection; although the important role of 99Tc(m)-HMPAO-labeled granulocyte scintigraphy has been recently emphasized. The aim of this study was to determine the sensitivity and specificity of 99m-technetium-hexamethylpropyleneamine oxime (99Tc(m)-HMPAO)- or 111In-oxine-labeled granulocyte scintigraphy for the diagnosis of infection in pancreatic or peripancreatic necrosis to define the ideal label for diagnosis. Thirty-six scintigraphic examinations were performed in 34 consecutive patients (mean age, 58 +/- 2 years) 20 +/- 2 days after the onset of acute pancreatitis (Balthazar classes A-C, n = 7; classes D and E, n = 29). The scintigraphic study included scintigraphic tomography and static acquisition 1 and 3 h, respectively, after reinjection of the autologous 99Tc(m)-labeled granulocytes and static images 3-4 and 24 h after the simultaneous reinjection of 111In-oxine-labeled autologous granulocytes. The diagnosis of infected pancreatic or peripancreatic necrosis was confirmed with percutaneous CT-guided aspiration (14 positive aspirates among 20 performed) and sterile necrosis after negative aspiration (6 negative aspirates) or after a 6 +/- 1-month follow-up free of clinical or biological signs of ongoing sepsis. The sensitivity and specificity were 86 and 73%, respectively, for scintigraphic tomography, 100 and 55% for 3-h 111In images, 93 and 68% for 3-4-h 111In images, and 100 and 64% for 24-h 111In images. The fall in splenic activity between the 3-4 and the 24-h 111In images was 26 +/- 3% in patients with septic pancreatic and peripancreatic necrosis (n = 14) and 16 +/- 3% in those with sterile necrosis (n = 22) (p